Certain 4 - amino - 2-(5-nitro-2-thienyl) quinazolines and the intermediate 4 - chloro-(5 - nitro-2-thienyl)quinazolines therefor

ABSTRACT

A SERIES OF 4-AMINO-2-(5-NITRO-2-THIENYL)QUINAZOLINES OF THE FORMULA:   2-(2-(O2N-)THIEN-5-YL),4-(R1-N(-R)-),6-R2-QUINAZOLINE   WHEREIN R IS HYDROXY (LOWER) ALKYL, DIHYDROXY (LOWER) OR MORPHOLINOPROPYL; R1 IS HYDROGEN, AMINO, OR HYDROXY (LOWER ALKYL); R2 IS HYDROGEN OR CHLORO; AND R AND R1 TAKEN TOGETHER WITH -N IS N-HYDROXYETHYLPIPERAZINO POSSESS ANTHELMINTIC ACTIVITY AGAINST ASCARIS SUUM AND SYPHACIA OBVELATA WHEN PERORALLY ADMINISTERED TO INFECTED MICE. THE MEMBERS OF THE SERIES ARE READILY PREPARED BY REACTING 4-CHLORO-2-(5-NITRO-2-THIENYL)QUINAZOLINE WITH THE APPROPRIATE AMINE.

United States Patent 3,705,898 CERTAIN 4 AMINO Z-(S-NITRO-Z-THIENYL) QUINAZOLINES AND THE INTERMEDIATE 4 CHLORO-(S NlTRO-2-THIENYL)QUINAZO- LINES THEREFOR Robert J. Alaimo, Norwich, N.Y., assiguor to Morton-Norwich Products, Inc. No Drawing. Filed Jan. 26, 1970, Ser. No. 5,924 Int. Cl. C07d 99/06 US. Cl. 260247.1 14 Claims ABSTRACT OF THE DISCLOSURE A series of 4-amino-2-(S-nitro-Z-thienyl)quinazolines of the formula:

wherein R is hydroxy (lower) alkyl, dihydroxy (lower) or morpholinopropyl; R is hydrogen, amino, or hydroxy (lower alkyl); R is hydrogen or chloro; and R and R taken together with -N is N-hydroxyethylpiperazino possess anthelmintic activity against Ascaris suum and Syphacia obvelata when perorally administered to infected mice. The members of the series are readily prepared by reacting 4-chloro-2-(5-nitro-2-thienyl)quinazoline with the appropriate amine.

This invention relates to chemical compounds. More particularly this invention is concerned with 4-amino-2- (S-nitro-Z-thienyl)quinazolines of the formula:

17 OzN C ("J wherein R is hydroxy (lower) alkyl, dihydroxy (lower) alkyl, hydroxy (lower) alkoxy (lower) alkyl, (lower) alkyl or morpholinopropyl; R is hydrogen, amino, or hydroxy (lower) alkyl; R is hydrogen or chloro; and R and R taken together with N is N-hydroxyethylpiperazino. It is also concerned with the compound 4-chloro-2- (5-nitro-2-thienyl)quinozoline useful as an intermediate in the preparation of the substituted amino compounds.

The compounds of Formula I are valuable antimicrobial agents. They are particularly noteworthy as anthelmintics. Thus, when administered perorally to mice infected with Ascaris suwm or Syphacia obvelata in doses ranging from 100 to 300 mg./kg. B.I.D. for a period up to five days, effective reduction of the parasite in the host is achieved. For oral administration usual pharmaceutical dosage forms are employed such as tablets, boluses, capsules, suspensions, and solutions wherein the excipients are those known to the pharmaceutical art and with which there is no incompatibility. The feed supply of animals is also a convenient carrier.

3,705,898 Patented Dec. 12, 1972 The method which is currently preferred for preparing the compounds of this invention consists in bringing together the 4-chloro-2-(5-nitro-2-thienyl) quinazoline and the appropriate amine. In eliecting this reaction an inert solvent such as dimethylformamide is advantageously employed. Heating the mixture serves to hasten the completion of the reaction.

In order that this invention may be readily understood by and available to those skilled in the art these illustrative examples are appended:

EXAMPLE I 4- (2-hydroxyethylamino) -2- (S-nitro-Z-thienyl) quinazoline (A) 1,2-dihydro-2-(5-nitro 2 thienyl)quinazolin-4 (3H)-one.A solution of 5-nitro-2-thiophene carboxaldehyde (157.0 g., 1.0 mole) in ethanol (1000 ml.) was warmed on a steam bath and treated with 20 ml. of cone. HCl. To it was added with rapid stirring a warm solution of anthranilamide 136.0 g., 1.0 mole) in ethanol (500 ml). The reaction mixture was heated on a steam bath and stirred for 1 hour, then chilled in ice and filtered. The product was washed with aqueous ethanol and air dried (227 g. 82.5%). Recrystallization from ethanol yielded needles which melted at 21922l.

Analysis.Calcd. for C H N O S (percent): C, 52.35; H, 3.29; N, 15.26. Found (percent): C, 52.60; H, 3.55; N, 15.10.

(B) 2-(5-nitro 2 thienyl)quinazolin-4(3H)one.-A mixture of (A) (245 g., 0.89 mole) and p-benzoquinone g., 1.11 mole) in ethanol (1500 ml.) and dimethyl-. formamide (600 ml.) was boiled under reflux with stirring for 6 hours. After chilling, the product was removed by filtration and stirred in ethanol (1000 ml.). Filtration and ether wash provided a yellow solid g., 66%). Recrystallization from dimethylformamide/H O provided needles which melted at 350-351.

Analysis.-Calcd. for C H N O S (percent): C, 52.74; H, 2.58; N, 15.38. Found (percent): C, 52.47; H, 2.61; N, 15.23.

(C) 4-chloro2-(5-nitro-2-thienyl)quinazoline.-To a solution of (B) (68.0 g., 0.25 mole) in phosphorus oxychloride (500.0 ml.) was added phosphorus pentachloride (68.0 g., 0.33 mole). The mixture was stirred and boiled under reflux until all material went into solution, then heated for an additional 15 minutes. After cooling overnight at room temperature, the light brown material was removed -by filtration and washed thoroughly with petroleum ether to give 65.0 g. (89.0%). Recrystallization from nitromethane provided crystals melting at 187- 189.

Amalysis.0alcd. for C H ClN O S (perofent): C, 49.40; H, 2.07; N, 14.41. Found (percent): C, 49.19; H, 2.08; N, 14.43.

(D) 4(2-hydroxyethylamino) 2 (5-nitro-2-thienyl) quinazoline.-A mixture of (C) (50 g., 0.17 mole) and ethanolamine (24 g., 0.40 mole) in dimethylformamide (500 ml.) was heated on a steam bath with stirring for 5.5 hours. After treatment with charcoal, the hot solution was filtered and poured onto ice.

The precipitated product (45 g., 83%) was recrystallized from ethanol to give yellow crystals which melted at 213-215".

3 Analysis.-Calcd. for C I-I N O S (percent): C, 53.15; H, 3.82; N, 17.71. Found (percent): C, 53.34; H, 3.93; N, 17.46.

Other compounds of this invention can be prepared in a fashion similar to that shown in Example 1(1)). The

product was precipitated from the dimethylformamide solution with water and removed by filtration. After drying the product weighed 14.0 g. (62%). Recrystallization from methanol/dimethylformamide (H gave yellow crystals melting at 212-214". table herebelow shows the amme to be reacted with the 4-chloro 2 (5 nitro 2 thienyDquinazoline, the Analysls' calcd' for CH13C1N404S (percent): product therefrom and the melting point and the analyzed 47-31; 3-44; Found (Percent): 47-38; carbon, hydrogen and nitrogen percentage thereof: 1453- M.P., IExample Amine Product C. 0 H N II N-ethyl ethanolamine 4-ethyl(2-hydroxyethyDamino-2-(5-nitro-Z-thienyhquinazoline... 158-160 55.80 4. 71 16.45 III 4-an1ino-1-butanol 4-(4hydroxy-1-butylamino)-2-(5-nitro-2-thieny1)quinazoline..- 171-173 55.53 4.64 16.57 V N-(3-aminopropyDmorpholine 4-(a-morpholininopropylarnino)-2-(5-nltro-2-thienyl)quinazoline.- 202-204 66-82 6.06 17. 60 V Z-hydroxyethylpiperazine 4-[4-(2-hydroxyethyl)piperazino]-2-(5-nitro-2-thienyDquinazo- 283-284 46-47 4.62 14.95

line dihydrochloride hemihydrate.

VI 2,2-iminodiethanol 4-[bis(2-hydroxyethyl)arnino}-2-(5-nitro-2-thienyl)qulnazoliue- 175-178 53.14 4.11 15.5 VII 1-amino-2,&propanedio1 4-(2,3-dihydroxypropy1amino)-2-(b-nitro-2-thienyl)quinazohne--. 212-213 51-87 4.05 16.13 VIII Z-hydroxyethylhydrazine 4-(Z-hydroxyethyl-l-hydrazino)-2(5nitro-2-thienyl)quinaeoline- 192-194 50. 50 3.99 20.97 IX 2-[2-(El-aminopropoxy)ethoxflethanol- 4-ilifilgihgggggghoxy)ethoxy]propyl )amino -2-(5-mtro-2- 83-86 54.16 6.39 13.31

1 1 55.35 5.24 14.45 gizz: hihfiiii ifogfii fiuai1111;113:221il fiidi g iiifilifiii fiiihigii fi503 5 8 3212 3111331)- l igo 54.59 4.89 14.95 XII N-buty1ethauolamine-- 4-l i i tly fi 2 h ggroxyethy!)arnino-2-(5-nitrm2-thienyl)quinazoline- 137-139 57.84 6. 40 15. 05 XIII Ethanolpropanolemine 4-{2-hydroxyethyl(EX-hydroxypropyl)amiuo]-2-(6-nitro-2-thienyl)- 166-168 54.48 4. 81 15.00

quinazoline.

EXAMPLE XIV EXAMPLE XV 6-ehloro-4- (2,B-dihydroxypropylamino) 6-chloro-4- [his (B-hydroxyethyl) amino] -2- 2- 5 -nitro-2-thienyl) quinazoline (S-nitro-Z-thienyl) quinazoline (A) 1 1,2 dih dm 2 5 2 thienyl) mixture 33 g. (0.1 mole) of 4,6 -d1chloro-2-(5-n1tro-2- quinazo1in-4-(3H)-one.- warm solution of 171 g. (1.0 thlenyl) qlflnazo'llne In 3 00 m1. of dlmethylformamide was mole) f 2 amino 5 ch1or0benzamide in 2500 1 f treated with 21 g. (0.2 mole) of bisethanolamme. The ethanol was treated with a warm solution of 157 g. (1.0 P P was heated a Steam bath for 4 Wlth mole) of 5-nitro-2-thiophenecarboxalclehyde in 500 ml. Surfing before muting f Water' P the of ethanol. The mixture was heated on a steam bath for P was collected meltmg at 160-165 m a Yleld of 1 hour. The resulting solution was cooled in the refrig- 35 32 (81%); erator overnight and the product was collected by filtra- Bi gs a gg iggg from mtmmethane gave a meltmg tion in a old of 208 67% Rec stallization from P0111 ethanol z needles j f at 8 Analysis.-Calcd. for C H ClN O S (percent): C,

Analysis. calcd' for cmHBClNaOsS C 48.67; H, 3.83; N, 14.19. Found (percent): C, 48.29; 46.53; H, 2.60; N, 13.57. Found (percent): 0, 46.42; H, 4.0 A 1 N, What is claimed is:

(B) 6-chloro-2-(5 nitro-2-thienyl)quinazolin-4(3H)- A compound of the formula: one.A mixture of 200 g. (0.65 mole) of 6-chloro-1,2- X dihydro 2 (S-nitro 2 thienyl)quinazolin-4(3H)- A one in 1500 ml. of ethanol and 108 g. (1.0 mole) of f C R: p-benzoquinone was refluxed with stirring for 8 hours. I 4} The mixture was cooled overnight. The product was col- S lected by filtration, rinsed with ethanol, and was air dried N I to give 140 g. (71%). Wherem X is I l 1 Recrystallization from dimethylformamide gave yellow R needles melting at 350 dec.

Analysis.Calcd. for C H ClN O S (percent): C,

46.84; H, 1.97; N, 13.66. Found (percent): C, 46.87; R1 H, 1.95; N, 13.66. in which R is hydroxy (C -C )alkyl, dihydroxy propyl,

(C) 4,6-dich1oro 2 (S-nitro-Z-thienyl)quinazoline. 2-hydroxyethoxy ethoxypropyl, (C -CQaIkyI or morpho- A mixture of 140 g. (0.45 mole) of 6-chloro-2-(5-nitro-2- linopropyl; R is hydrogen, amino, or hydroxy (C -C thienyl)quinazolin-4(3H)-one in 1000 ml. of phosphorus alkyl; R is hydrogen or chloro; and R and R taken oxychloride and 150 g. (0.72 mole) of phosphorus pentogether with --N is N-hydroxye-thylpiperazino. tachloride was heated to reflux, with stirring, for 15 min- 2. The compound 4-(2-hydroxyethylamino)-2-(5-nitroutes after completion of solution. The mixture was cooled Z-thienyl) quinazoline. in an ice bath and a tan solid was collected by filtration 3. The compound 4-ethyl(2-hydroxyethylamino)-2 in a yield of 107 g. The filtrate was diluted with hexane (5-nitro-2-thienyl)quinazoline. and was filtered to give 21 g. The total yield was 128 g. 4. The compound 4-(4-hydroxy-l-butylamino)-2-(5- 87% nitro-2-thienyl) quiuazoline.

Recrystallization from nitromethane gave a solid melt- 5. The compound 4-(3-morpholinopropylamino)-2-(5- ing at 167-169. nitro-Z-thienyl)quinazoline.

Analysis.-Calcd. for C 'H Cl N O S (percent): C, 6. The compound 4-[4-(2-hydroxyethyl)piperazino]-2- 44.l9; H, 1.55; N, 12.87. Found (percent): C, 44.21; H, (S-nitro-Z-thienyDquinazoline dihydrochloride hemihy- 1.53; N, 12.75. drate.

(D) 6-ehloro 4 (2,3-dihydroxypropylamino) 2 (5- 7. The compound 4-[bis(2-hydroxyethyl)amino] -2-(5- nitro-Z-thienyl) quinazoline.-A dimethylformamide solunitro-Z-thienyl) quinazoline. tion (200 ml. of the chloro compound from part (C) 8. The compound 4-(2,3-dihydroxypropylamino)-2-(5- (20 g., 0.06 mole) and 1-amino-2,3-propanediol (11 g., nitro-2-thienyl)quinazoline.

0.12 mole) was heated on steam bath for 3 hours. The 9. The compound 4-(2-hydroxyethyl-l-hydrazino)-2.-(5 mixture was then treated with charcoal and filtered. The nitro-l-thienynquinazoline.

5 6 10. The compound 4- 3{2-[(2hydroxyethoxy)eth- References Cited oxy] propyl}amino -2-(S-nitro-Z-thienyl) quinazoline. UNITED STATES PATENTS 11. The compound 4-(bis-2-hydroxypropy1amino)-2- (smitroafllienyl)quinazofine. 3,073,826 1/ 1963 Scarborough 260-256.5 R

12. The compound 4-[Z-hydroxyethyl(Z-hydroxypro- 5 pyl)amino]-2-(5-nitro-2-thienyl) quinazoline. NICHOLAS RIZZO Pnmary Exammer 13. The compound 4-butyl(2-hydroxyethyl) amino-Z- R. J. GALLAGHER, Assistant Examiner (5 -nitro-2-thienyl) quinazoline.

14. The compound 4-[2-hydroxyethyl(3-hydroxypropyl)amino1-2-(5-nitro-2-thieny1) quinazoline. 10 260251 Q, 256.5 R 

